(a) Field of the Invention
The present invention relates to a novel process for the preparation of an .alpha.-alkoxy acetic acid having the general formula ##STR2## or a salt thereof, wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and are hydrogen, alkyl, alkoxy, halo, phenyl, substituted phenyl, or hydroxy; A is sulfur, oxygen, or --CH.sub.2 --; and Alk is straight or branched chain alkylene; which comprises reacting a compound of the formula ##STR3## wherein R.sup.1, R.sup.2, R.sup.3, A, and Alk are defined as above, with a suitable base in an aprotic organic solvent followed by reaction of the resulting alkoxide with a tert-alkyl monohaloacetic acid ester to generate an alkoxyacetate ester which is then reacted with an appropriate hydrogen halide, organic acid or Lewis acid in nitromethane to give the .alpha.-alkoxy acetic acid product. Reaction of this product with an appropriate base gives an .alpha.-alkoxyacetic acid salt.
The process of the present invention is especially useful for preparing phenylthio-.alpha.-alkoxy acetic acids. This process is also especially useful for preparing single isomers of the products because one or more chiral centers contained within the Alk chain or the A function are not disturbed by this basic process. In some cases, chiral compounds are preferred over the racemic or enantiomeric mixtures for pharmaceutical or other uses. Therefore, processes which aid in the preparation of single isomers are very advantageous.
(b) Background Information
U.S. Pat. Nos. 4,711,903 and 4,755,524 disclose a method of preparing a [2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-alkoxy]acetic acid from a 2,6-bis (1,1-dimethylethyl)-4-[(2-hydroxyalkyl) thio]phenol by a process in which chloroacetic acid is added to the alcohol in t-butyl alcohol which is a protic solvent, then potassium tert-butoxide is added, and the mixture is refluxed. This method gives yields of less than 5% and thus is not a very efficient process.
U.S. Pat. No. 4,804,777 discloses a process for the preparation of an aryloxy acetic acid by oxidation of an aryloxyethanol in an aqueous alkaline reaction medium at a temperature in the range of 0.degree. C. to the boiling point of the reaction medium in the presence of a catalytic amount of a catalyst comprised of palladium, silver, and optionally antimony, and carbon to form the corresponding alkali metal ester and contacting the alkali metal with a mineral acid. Metal catalysts can scramble hydrogen atoms or carbon atoms and chirality can be lost. In addition, they can either abstract or be poisoned by sulfur.
U.S. Pat. No. 3,918,899 discloses a method of preparing carboxymethylated cottons in non-aqueous media by reacting anhydrous sodium cellulosate with a salt of a monochloroacetate in an anhydrous DMSO solution.
R. C. Fuson and B. H. Wojcik, ORGANIC SYNTHESIS COLLECTED VOLUMES, 2:260-262(1943) discloses a three-step method for preparing ethoxyacetic acid from ethanol which is the substrate and the solvent (protic solvent).
D. J. Abraham, et al., J. MED. CHEM., 27:1549-1559 (1984) discloses alkylation of the phenolic hydroxyl group in 2-hydroxy-4-nitromethylbenzoate by reacting it with BrCH.sub.2 COO-Bu-t in the presence of NaH in tetrahydrofuran (THF). Phenolic hydroxyl groups are acidic.
E. C. Taylor, et al., J. ORG. CHEM. 53:35-38 (1988) at page 36 discloses selective removal of a tert-butyl ester from a pterin of the formula ##STR4## using gaseous hydrogen chloride in nitromethane to give 2-pivaloyl-10-deazapteroic acid having the formula ##STR5##